Uveitis comprises of a group of diseases associated with inflammation of the eye that can lead to vision loss. Some people with uveitis also have macular edema (swelling of the retina at the back of the eye). Uveitis and macular edema are treated with medications and sometimes surgery, but treatment does not always prevent vision loss. Previous research has shown that injections of methotrexate into the eye of people with eye disease other than uveitis can help relieve the inflammation, or swelling, that causes macular edema and can slow visual loss. However, it has not yet been approved as a treatment for macular edema associated with uveitis.

OBJECTIVES:

To evaluate the safety and effectiveness of methotrexate injections as a treatment for macular edema associated with uveitis.

ELIGIBILITY:

Individuals at least 18 years of age who have been diagnosed with uveitis and macular edema in at least one eye.

DESIGN:

This study requires at least nine visits to the National Eye Institute study clinic over a period of 6 months (24 weeks).

Participants will be screened with a physical and ophthalmic examination, medical history, blood and urine tests, and additional eye and other tests as needed.

Participants will receive a methotrexate injection in a selected treatment eye. After the injection, participants will receive antibiotic eye drops to place in the eye three times a day for the 3 days following the injection, leucovorin (folic acid) drops to place in the eye four times a day for 1 week following the injection, and a dose of folic acid to be taken by mouth the day after the injection.

Participants who tolerate the initial injection may continue to receive injections in their study eye every month for 6 months. After 6 months, participants who show improvement from the injections may be evaluated to receive additional injections every 4 to 8 weeks until researchers end the study.

Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:

Number of Participants Who Meet the Definition of Treatment Success Within 12 Weeks From Baseline. [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]

Treatment success is defined as achieving at least a 1-step decrease in the LogScore scale for central macular thickness.

A decrease of at least 1-step on the logOCT scale, where Change in logOCT=log(follow-up thickness/200) - log(baseline thickness/200) is considered clinically significant. A 1-step decrease is equivalent to at least a 20% improvement of central macular thickness and represents greater than twice the variability of retinal thickness measurements (approximately 25-30 µ).

Examples of OCT measurements with their corresponding LogScore, where LogScore=10xlogOCT are as follows:

The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the "choice of study eye in cases of bilateral disease" selection criteria outlined in the eligibility criteria.

The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the "choice of study eye in cases of bilateral disease" selection criteria outlined in the eligibility criteria.

The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the "choice of study eye in cases of bilateral disease" selection criteria outlined in the eligibility criteria.

The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the "choice of study eye in cases of bilateral disease" selection criteria outlined in the eligibility criteria.

The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the "choice of study eye in cases of bilateral disease" selection criteria outlined in the eligibility criteria.

The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the "choice of study eye in cases of bilateral disease" selection criteria outlined in the eligibility criteria.

The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the "choice of study eye in cases of bilateral disease" selection criteria outlined in the eligibility criteria.

The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the "choice of study eye in cases of bilateral disease" selection criteria outlined in the eligibility criteria.

The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the "choice of study eye in cases of bilateral disease" selection criteria outlined in the eligibility criteria.

The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the "choice of study eye in cases of bilateral disease" selection criteria outlined in the eligibility criteria.

The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the "choice of study eye in cases of bilateral disease" selection criteria outlined in the eligibility criteria.

The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the "choice of study eye in cases of bilateral disease" selection criteria outlined in the eligibility criteria.

Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20.

The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the "choice of study eye in cases of bilateral disease" selection criteria outlined in the eligibility criteria.

Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20.

The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the "choice of study eye in cases of bilateral disease" selection criteria outlined in the eligibility criteria.

Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20.

The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the "choice of study eye in cases of bilateral disease" selection criteria outlined in the eligibility criteria.

Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20.

The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the "choice of study eye in cases of bilateral disease" selection criteria outlined in the eligibility criteria.

Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20.

The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the "choice of study eye in cases of bilateral disease" selection criteria outlined in the eligibility criteria.

Visual acuity was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Acuity is measured as letters read on an ETDRS eye chart and the letters read equate to Snellen measurements. For example, if a participant reads between 84 and 88 letters, the equivalent Snellen measurement is 20/20.

The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the "choice of study eye in cases of bilateral disease" selection criteria outlined in the eligibility criteria.

Number of Participants Presenting No Change in the Area of Leakage in the Study Eye as Seen on Fluorescein Angiography (FA) Imaging at Week 12 as Compared to Baseline [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]

Fluorescein angiography (FA) images were obtained via a standard digital imaging system (OIS, Sacramento, CA). Three retinal specialists independently graded the area of late fluorescein leakage (at approximately 10 minutes) in each eye using a region-of-interest tool in an image analysis software package (NIH ImageJ, Bethesda, MD).

The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the "choice of study eye in cases of bilateral disease" selection criteria outlined in the eligibility criteria.

Number of Participants Presenting No Change in the Area of Leakage in the Study Eye as Seen on Fluorescein Angiography (FA) Imaging at Week 24 as Compared to Baseline [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]

Fluorescein angiography (FA) images were obtained via a standard digital imaging system (OIS, Sacramento, CA). Three retinal specialists independently graded the area of late fluorescein leakage (at approximately 10 minutes) in each eye using a region-of-interest tool in an image analysis software package (NIH ImageJ, Bethesda, MD).

The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the "choice of study eye in cases of bilateral disease" selection criteria outlined in the eligibility criteria.

Number of Participants Presenting the Same Autofluorescence Patterns in the Study Eye as Seen on Fundus Autofluorescence (FAF) Imaging at Week 12 as Observed at Baseline [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]

The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the "choice of study eye in cases of bilateral disease" selection criteria outlined in the eligibility criteria.

Number of Participants Presenting the Same Autofluorescence Patterns in the Study Eye as Seen on Fundus Autofluorescence (FAF) Imaging at Week 24 as Observed at Baseline [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]

The participant's eye that met the study eye eligibility criteria was selected as the study eye. For cases in which both eyes met the study eye eligibility criteria, the study eye was selected according to the "choice of study eye in cases of bilateral disease" selection criteria outlined in the eligibility criteria.

Number of Participants Experiencing a Complete Resolution of Fluid as Seen on OCT at Any Time During the Study Period [ Time Frame: Baseline and Week 74 ] [ Designated as safety issue: No ]

Observation of Dose Reduction of Systemic Immunosuppression or Steroids Over the Course of the Study Period [ Time Frame: Baseline and Week 74 ] [ Designated as safety issue: Yes ]

400 μg/100 μL monthly injections for the first 3 months, then as needed per the treatment criteria

Detailed Description:

OBJECTIVE:

The study objective is to investigate the safety, tolerability and potential efficacy of intravitreal injections of methotrexate as a possible treatment for chronic macular edema secondary to panuveitis, posterior or intermediate uveitis.

STUDY POPULATION:

Five participants with chronic macular edema associated with panuveitis, posterior or intermediate uveitis will be initially enrolled. However, up to an additional two participants may be enrolled to account for participants who withdraw from the study prior to reaching Week 12. Eligibility criteria include macular edema in the study eye, which has not been responsive to conventional immunosuppressive therapy in the past three months, or the participant experienced a recurrence of macular edema while on conventional immunosuppressive therapy.

STUDY DESIGN:

In this single-center, prospective, uncontrolled, unmasked, Phase I/II clinical trial, intravitreal injections of methotrexate at a dose of 400 μg per 100 μL will be administered. There will be an induction phase and a pro re nata (PRN) phase. During the induction phase, participants will receive injections at baseline and Weeks 4, 8, 12, 16 and 20 in their study eye unless contraindicated. Additional safety visits will occur at Weeks 1 and 2. Beginning at Week 24, participants who agree to remain in the study will undergo evaluation for injection in the study eye PRN every 4-8 weeks. These participants will be followed for 4-8 weeks after the last enrolled participant completes his/her Week 24 visit.

OUTCOME MEASURES:

The primary outcome is the number of participants who meet the definition of treatment success within 12 weeks from baseline. Treatment success is defined as achieving at least a 1-step decrease in the LogScore scale for central macular thickness. Secondary outcomes include changes in Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA), changes in excess retinal thickening, changes in macular thickness, changes in intraocular inflammation on clinical exam, changes in leakage as seen on fluorescein angiography (FA), changes in autofluorescence patterns seen on fundus autofluorescence (FAF) imaging and observation of dose reductions of systemic immunosuppression or steroids. Safety outcomes include the number and severity of adverse events, systemic and ocular toxicities, electrophysiologic changes assessed by full-field electroretinography (ERG) and number of withdrawals.

Eligibility

Ages Eligible for Study:

18 Years and older

Genders Eligible for Study:

Both

Accepts Healthy Volunteers:

No

Criteria

INCLUSION CRITERIA:

Participant must be 18 years of age or older.

Participant must understand and sign the protocol's informed consent document.

Participant is willing to comply with the study procedures and return for all study visits.

Participant has chronic macular edema secondary to non-infectious panuveitis, posterior or intermediate uveitis in at least one eye (the study eye) that has:

not been responsive to conventional immunosuppressive therapy in the past 3 months; OR

recurred while on conventional immunosuppressive therapy.

Participant has central macular thickness of ≥ 270 microns in the study eye.

Participant has visual acuity of 20/400 or better (≥ 19 ETDRS letters) in the study eye.

Female participants of childbearing potential must not be pregnant or breast-feeding, must have a negative serum pregnancy test at screening and must be willing to undergo serum pregnancy tests throughout the study.

Both female participants of childbearing potential (see Appendix 1 for definition) and male participants able to father children must have (or have a partner who has) had a hysterectomy or vasectomy, be completely abstinent from intercourse or must agree to practice two acceptable methods of contraception throughout the course of the study and for six months after the last study medication injection. Acceptable methods of contraception include:

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01314417